The incidence of hepatocellular carcinoma (HCC) is two to four times higher in men than in women and the progression of chronic liver diseases to cirrhosis is much faster in men than in women. These suggest an important role of sex hormones in hepatocarcinogenesis. However, the molecular mechanism underlying the gender disparity in HCC still remains poorly understood. And there have been controversies on the use of hormonal therapies for patients with HCC. Hence, a better understanding of the genetic and epigenetic alterations that contribute to HCC development, especially to the gender disparity of HCC, may lead to a discovery of new etiologic, prognostic or therapeutic targets. The long- term goal is to understand how the genetic alterations in cells lead to hepatocarcinogenesis. The objective of this proposal is to determine the mechanism by which down regulation of nuclear receptor coactivator 5 (Ncoa5) contributes to the development of HCC. The central hypothesis is that Ncoa5 deficiency preferentially promotes hepatocarcinogenesis in males through inhibition of estrogen receptor 1 (ER?) activity and upregulation of androgen receptor (AR) expression in the liver. This hypothesis has been formulated on the basis of our recent preliminary data. The rationale for the proposed research is that understanding of the mechanism underlying Ncoa5-mediated suppression of HCC will reveal a novel regulatory pathway and new targets for developing innovative strategies to the prevention and treatment of HCC. This hypothesis will be tested by the following two specific aims: 1). Determine the effects of estrogen on Ncoa5 deficiency induced hepatocarcinogenesis using a novel genetically-engineered mouse model; and 2) Determine the molecular mechanism by which Ncoa5 exerts its effect on Kupffer cells and hepatocytes. The approach is innovative, because it utilizes a novel genetically-engineered mouse model of spontaneous HCC to prove a critical role of Ncoa5 in the suppression of HCC development. The proposed research is significant, because it is expected to demonstrate Ncoa5 as a novel mouse tumor suppressor with haploinsufficiency that links up ER? and AR mediated regulatory pathways to HCC. This will not only advance our understanding of the etiological mechanisms of HCC, but also provide the fields of basic and preclinical studies with a new mouse model that mimics the initiation and progression of human HCC.